Fewer than 30 percent of diabetic patients get irreversible nephropathy. For diabetic relatives of patients with nephropathy the risk is 3.5 to 10-fold higher than the general population. Thus, genetic susceptibility appears to distinguish those diabetic patients destined to develop nephropathy. We propose to map diabetes susceptibility genes using an approach that combines nonparametric sib pair analysis of concordant and discordant sibs, allelic association, and quantitative trait analysis in families with multiple diabetic siblings. Linkage will be tested in 150 sib pairs concordant for diabetes and 75 discordant for diabetes. Linkage and association will first be tested for known genes and proposed loci that influence risk of Type 2 diabetes, hypertension, nephropathy in other populations or animal models, and glycemic effects including aldose reductase. A 10 cM genome scan will be conducted to map novel genes. Potential nephropathy loci will be tested for association in 200 unrelated patients with nephropathy, and tested in an additional 100 concordant and 50 discordant sib pairs. Additional studies will map the quantitative trait locus controlling albumin excretion in diabetic patients using a variance component approach to linkage. Finally, transformed lymphocytes from diabetic and nondiabetic members of familial diabetes pedigrees will be studied under euglycemic and hyperglycemic conditions to search for preclinical markers of nephropathy. These studies will be conducted in families for which a genome search for diabetes susceptibility is in progress. Sorbitol accumulation and aldose reductase expression will be examined and tested for linkage to the aldose reductase locus. Sodium hydrogen exchange will be measured and tested for correlation with sodium hydrogen exchanger 1 message. A genome scan will be undertaken to map the quantitative trait locus controlling sodium hydrogen exchange, and to determine whether this locus leads to nephropathy. These studies will identify genes and chromosomal regions containing genes that predispose to nephropathy, and will lead to an improved understanding better management of diabetic nephropathy.